Technical Field
The instant invention relates to a method for detecting and measuring malaria infection by detecting and measuring TLR9-mediated, MyD88-dependent innate immune activity induced by hemozoin, hydrophobic heme polymers produced as a hemoglobin metabolite by malaria parasites; screening of a vaccine for malaria infection or a preventative or therapeutic agent for malaria infection using the method for detection and measurement; regulation of the induction of innate immunity using the hemozoin or synthetic hemozoin as an adjuvant or immunostimulant; a TLR9 agonist containing hemozoin, synthetic hemozoin or derivatives thereof as an active ingredient; and the like.
Background Art
Malaria infection is the major cause of disease and mortality of humans, especially in the tropical regions of the world. Due to a complex life cycle and rapid polymorphism of malaria parasites, host-parasite interactions and resulting innate immune responses to malaria parasites are still poorly understood despite the necessity of effective immunotherapies against malaria (Nat. Med. 4: 520-524, 1998; Nat. Rev. Immunol. 4: 169-180, 2004). Robust innate immune activation, including proinflammatory cytokine production in response to malaria parasites and/or a metabolite released from ruptured infected red blood cells, has been linked to the major symptoms such as high fever (Ann. Trop. Med. Parasitol. 91: 533-542, 1997). Recent evidence suggests that toll-like receptors (TLRs) are involved in innate immune responses to a variety of pathogens including Plasmodium (Annu. Rev. Immunol. 20: 197-216, 2002; Nat. Rev. Immunol. 4: 499-511, 2004).
In murine malaria infection, myeloid differentiation factor 88 (MyD88), an essential adaptor molecule for TLR-mediated cytokine production, was shown to be critical for IL-12 induction by Plasmodium berghei parasites that cause liver damage (J. Immunol. 167: 5928-5934, 2001). A recent study has reported that P. falciparum blood-stage parasites activate human plasmacytoid dendritic cells (DCs) and murine DCs through MyD88-dependent and TLR9-dependent pathways. Although the responsible molecule is yet unidentified, it is suggested that the molecule is a protein contained in schizont lysate or a complex thereof (J. Immunol. 172: 4926-4933, 2004).
Hemozoin (HZ), known as a malaria pigment, is a detoxification product of heme molecules persisting in food vacuoles of Plasmodium parasites (Int. J. Parasitol. 32: 1645-1653, 2002; Ann. Trop. Med. Parasitol. 91: 501-516, 1997). Intercellular HZ is released into blood during schizont rupture and phagocytosed by myeloid cells, which results in the concentration of HZ in the reticulo-endothelial system (Ann. Trop. Med. Parasitol. 91: 501-516, 1997). Specifically, malaria parasites in the red blood cells digest host hemoglobin to hydrophobic heme polymers known as HZ. Then the polymers are released into the blood stream, captured in the reticulo-endotherial system, and accumulate in the system. It has been reported that HZ produced from P. falciparum activates macrophages to produce proinflammatory cytokines, chemokines and nitrogen, and enhances the maturation of human myeloid dendritic cells (DCs) (J. Inflamm. 45: 85-96, 1995; Infect. Immun. 70: 3939-3943, 2002). These studies promoted the need for studying the molecular mechanism through which HZ activates innate immunity and for better understanding the malaria parasite-host interactions.    Non-patent document 1: Nat. Med. 4: 520-524, 1998    Non-patent document 2: Nat. Rev. Immunol. 4: 169-180, 2004    Non-patent document 3: Ann. Trop. Med. Parasitol. 91: 533-542, 1997    Non-patent document 4: Annu. Rev. Immunol. 20: 197-216, 2002    Non-patent document 5: Nat. Rev. Immunol. 4: 499-511, 2004    Non-patent document 6: J. Immunol. 167: 5928-5934, 2001    Non-patent document 7: J. Immunol. 172: 4926-4933, 2004    Non-patent document 8: Int. J. Parasitol. 32: 1645-1653, 2002    Non-patent document 9: Ann. Trop. Med. Parasitol. 91: 501-516, 1997    Non-patent document 10: J. Inflamm. 45: 85-96, 1995    Non-patent document 11: Infect. Immun. 70: 3939-3943, 2002